PotatoG-DKB: a potato gene-disease knowledge base mined from biological literature.

Background: Potato is the fourth largest food crop in the world, but potato cultivation faces serious threats from various diseases and pests. Despite significant advancements in research on potato disease resistance, these findings are scattered across numerous publications. For researchers, obtaining relevant knowledge by reading and organizing a large body of literature is a time-consuming and labor-intensive process. Therefore, systematically extracting and organizing the relationships between potato genes and diseases from the literature to establish a potato gene-disease knowledge base is particularly important. Unfortunately, there is currently no such gene-disease knowledge base available. Methods: In this study, we constructed a Potato Gene-Disease Knowledge Base (PotatoG-DKB) using natural language processing techniques and large language models. We used PubMed as the data source and obtained 2,906 article abstracts related to potato biology, extracted entities and relationships between potato genes and related disease, and stored them in a Neo4j database. Using web technology, we also constructed the Potato Gene-Disease Knowledge Portal (PotatoG-DKP), an interactive visualization platform. Results: PotatoG-DKB encompasses 22 entity types (such as genes, diseases, species, etc.) of 5,206 nodes and 9,443 edges between entities (for example, gene-disease, pathogen-disease, etc.). PotatoG-DKP can intuitively display associative relationships extracted from literature and is a powerful assistant for potato biologists and breeders to understand potato pathogenesis and disease resistance. More details about PotatoG-DKP can be obtained at https://www.potatogd.com.cn/.

Phosphoproteomic analysis reveals CDK5-Mediated phosphorylation of MTDH inhibits protein synthesis in microglia.

CDK5 plays a crucial role in maintaining normal central nervous system (CNS) development and synaptic function, while microglia are the primary immune cells present in the CNS and play vital physiological roles in CNS development, immune surveillance, and regulation of synaptic plasticity. Despite this, our understanding of both the substrate proteins and functional mechanisms of CDK5 in microglia remains limited. To address this, we utilized CRISPR-Cas9 knockout of Cdk5 in BV2 cells and conducted quantitative phosphoproteomics analysis to systematically screen potential CDK5 substrates in microglia. Our findings identified 335 phosphorylation sites on 234 proteins as potential CDK5 substrates in microglia based on the reported sequence motif. Through in vitro kinase assay and intracellular inhibition and knockout of CDK5 experiments, we confirmed that ER proteins MTDH (protein LYRIC) and Calnexin are novel substrate proteins of CDK5. Moreover, we demonstrated for the first time a critical mechanism for regulating protein synthesis in microglia, that the phosphorylation of S565 site on MTDH, a key protein mediating cell growth, by CDK5 inhibits protein synthesis. Our data provide valuable insights for the discovery of new substrate proteins of CDK5 and the in-depth investigation of the function and mechanism of CDK5 in microglia.

Functional Aptamers In Vitro Evolution for Intranuclear Blockage of RNA-Protein Interaction.

Over the last 30 years, despite considerable research and endeavors aimed at harnessing aptamers as pharmaceutical molecules, the progress in developing aptamer-based drugs has been falling short of expectations. Sequential steps of affinity molecule acquisition and functional screening are typically required for discovering affinity-based macromolecule therapeutics, which can be time-consuming and limiting in candidate selection. Additionally, aptamers often necessitate tedious postselection modifications to overcome pharmacokinetic limitations, which usually impede the binding affinity. Herein, we propose a novel in vitro screening platform termed Functional Aptamers in vitro Evolution (FAIVE), which integrates affinity molecule acquisition with functional screening and introduces chemical diversity during the process. This platform aims to rapidly generate functional aptamers capable of binding to target proteins and regulating their functions. Illustrated by targeting intranuclear RNA-protein interactions involving HIV-1 Tat protein and TAR RNA, FAIVE demonstrates a selection of functional aptamers with significant intracellular blocking effects. The study also explores lipid nanoparticle delivery systems to enhance intracellular delivery efficiency, expanding aptamer targeting potential to broader intracellular and intranuclear domains. This study emphasizes the potential of FAIVE to expedite the development of aptamer-based drugs and facilitate the creation of more versatile and effective therapeutics.

EEGNet classification of sleep EEG for individual specialization based on data augmentation.

Sleep is an essential part of human life, and the quality of one's sleep is also an important indicator of one's health. Analyzing the Electroencephalogram (EEG) signals of a person during sleep makes it possible to understand the sleep status and give relevant rest or medical advice. In this paper, a decent amount of artificial data generated with a data augmentation method based on Discrete Cosine Transform from a small amount of real experimental data of a specific individual is introduced. A classification model with an accuracy of 92.85% has been obtained. By mixing the data augmentation with the public database and training with the EEGNet, we obtained a classification model with significantly higher accuracy for the specific individual. The experiments have demonstrated that we can circumvent the subject-independent problem in sleep EEG in this way and use only a small amount of labeled data to customize a dedicated classification model with high accuracy.

CD36+ pro-inflammatory macrophages interact with ZCCHC12+ tumor cells in papillary thyroid cancer promoting tumor progression and recurrence.

Local recurrence and distal metastasis negatively impact the survival and quality of life in patients with papillary thyroid cancer (PTC). Therefore, identifying potential biomarkers and therapeutic targets for PTC is clinically crucial. In this study, we performed a multi-omics analysis that identified a subset of CD36+ pro-inflammatory macrophages within the tumor microenvironment of PTC. The recruitment of CD36+ macrophages to pre-malignant regions strongly correlated with unfavorable outcomes in PTC and the presence of tumor-infiltrating CD36+ macrophages was determined to be a risk factor for recurrence. The CD36+ macrophages exhibited interactions with metabolically active ZCCHC12+ tumor cells. By secreting SPP1, the CD36+ macrophages activated the PI3K-AKT signaling pathway, thereby promoting proliferation of the cancer cells. Dysregulation of iodine metabolism was closely related to the acquisition of the pro-inflammatory phenotype in macrophages. Iodine supplementation inhibited the activation of pro-inflammatory signaling and impeded the development of CD36+ macrophages by enhancing DUSP2 expression. Overall, our findings shed light on the intricate crosstalk between CD36+ macrophages and ZCCHC12+ tumor cells, providing valuable insights for the treatment and prognosis of PTC.

RNA-binding protein PTENα blocks RIG-I activation to prevent viral inflammation.

A timely inflammatory response is crucial for early viral defense, but uncontrolled inflammation harms the host. Retinoic acid-inducible gene I (RIG-I) has a pivotal role in detecting RNA viruses, yet the regulatory mechanisms governing its sensitivity remain elusive. Here we identify PTENα, an N-terminally extended form of PTEN, as an RNA-binding protein with a preference for the CAUC(G/U)UCAU motif. Using both in vivo and in vitro viral infection assays, we demonstrated that PTENα restricted the host innate immune response, relying on its RNA-binding capacity and phosphatase activity. Mechanistically, PTENα directly bound to viral RNA and enzymatically converted its 5'-triphosphate to 5'-monophosphate, thereby reducing RIG-I sensitivity. Physiologically, brain-intrinsic PTENα exerted protective effects against viral inflammation, while peripheral PTENα restricted host antiviral immunity and, to some extent, promoted viral replication. Collectively, our findings underscore the significance of PTENα in modulating viral RNA- and RIG-I-mediated immune recognition, offering potential therapeutic implications for infectious diseases.

Advancing vaccine development: Evaluation of a mannose-modified lipid nanoparticle-based candidate for African swine fever p30 mRNA vaccine eliciting robust immune response in mice.

The African swine fever virus (ASFV) continues to pose significant economic and pandemic risks. Consequently, discovering new, efficient vaccines is crucial. Messenger RNA (mRNA) vaccines have emerged as promising candidates, providing minimal risk of insertional mutagenesis, high safety profiles, effectiveness, rapid scalability in production, and cost-effectiveness. In this study, we have developed an ASF p30 mRNA vaccine candidate (mRNA/Man-LNP) employing mannose-modified lipid nanoparticles (LNPs). The mRNA/Man-LNP exhibited effective antigen presentation and facilitated dendritic cells (DCs) maturation. Notably, it elicited strong IgG titers and activated CD4+ and CD8+ T-cells in immunized mice, all while adhering to stringent biosafety standards. This investigation demonstrates that mRNA/Man-LNP can trigger both humoral and cellular immune responses, suggesting its potential as a potent and promising vaccine candidate for controlling African swine fever (ASF).

Identifying potential breath biomarkers for early diagnosis of papillary thyroid cancer based on solid-phase microextraction gas chromatography-high resolution mass spectrometry with metabolomics.

INTRODUCTION: Thyroid cancer incidence rate has increased substantially worldwide in recent years. Fine needle aspiration biopsy (FNAB) is currently the golden standard of thyroid cancer diagnosis, which however, is invasive and costly. In contrast, breath analysis is a non-invasive, safe and simple sampling method combined with a promising metabolomics approach, which is suitable for early cancer diagnosis in high volume population. OBJECTIVES: This study aims to achieve a more comprehensive and definitive exhaled breath metabolism profile in papillary thyroid cancer patients (PTCs). METHODS: We studied both end-tidal and mixed expiratory breath, solid-phase microextraction gas chromatography coupled with high resolution mass spectrometry (SPME-GC-HRMS) was used to analyze the breath samples. Multivariate combined univariate analysis was applied to identify potential breath biomarkers. RESULTS: The biomarkers identified in end-tidal and mixed expiratory breath mainly included alkanes, olefins, enols, enones, esters, aromatic compounds, and fluorine and chlorine containing organic compounds. The area under the curve (AUC) values of combined biomarkers were 0.974 (sensitivity: 96.1%, specificity: 90.2%) and 0.909 (sensitivity: 98.0%, specificity: 74.5%), respectively, for the end-tidal and mixed expiratory breath, indicating of reliability of the sampling and analysis method CONCLUSION: This work not only successfully established a standard metabolomic approach for early diagnosis of PTC, but also revealed the necessity of using both the two breath types for comprehensive analysis of the biomarkers.

An all-optical multidirectional mechano-sensor inspired by biologically mechano-sensitive hair sensilla.

Mechano-sensitive hair-like sensilla (MSHS) have an ingenious and compact three-dimensional structure and have evolved widely in living organisms to perceive multidirectional mechanical signals. Nearly all MSHS are iontronic or electronic, including their biomimetic counterparts. Here, an all-optical mechano-sensor mimicking MSHS is prototyped and integrated based on a thin-walled glass microbubble as a flexible whispering-gallery-mode resonator. The minimalist integrated device has a good directionality of 32.31 dB in the radial plane of the micro-hair and can detect multidirectional displacements and forces as small as 70 nm and 0.9 µN, respectively. The device can also detect displacements and forces in the axial direction of the micro-hair as small as 2.29 nm and 3.65 µN, respectively, and perceive different vibrations. This mechano-sensor works well as a real-time, directional mechano-sensory whisker in a quadruped cat-type robot, showing its potential for innovative mechano-transduction, artificial perception, and robotics applications.

N-C QDs coated with a molecularly imprinted polymer as a fluorescent probe for detection of penicillin.

Many diseases are due to bacterial infections, which are treated by penicillin. Existing methods for penicillin detection have relatively high requirements for sample storage and processing, personnel professionalism, and instruments. Herein, water-soluble N-C quantum dots (QDs) from wheat straw were synthesized in a green way by using an efficient and simple method. The N-C QDs were modified with an imprinted layer by a gel-sol method. Penicillin selectively quenched the fluorescence emission of N-C QDs@MIP, and a linear relationship was obtained in the concentration range of 1.0 × 10-6-15.2 × 10-6 mol L-1. The reliability of the sensor in real sample analysis was satisfactory with results in the range of 93.6%-100%, and the sensor showed good reproducibility and long-term stability. The study provides a simple strategy to fabricate N-C QDs@MIP with a highly selective recognition ability and opens an avenue to develop highly efficient sensing probes for the detection of antibiotics in biological applications.

Noninvasively Deciphering the Immunosuppressive Tumor Microenvironment Using Galectin-1 PET to Inform Immunotherapy Responses.

Immune checkpoint blockade (ICB) has achieved groundbreaking results in clinical cancer therapy; however, only a subset of patients experience durable benefits. The aim of this study was to explore strategies for predicting tumor responses to optimize the intervention approach using ICB therapy. Methods: We used a bilateral mouse model for proteomics analysis to identify new imaging biomarkers for tumor responses to ICB therapy. A PET radiotracer was synthesized by radiolabeling the identified biomarker-targeting antibody with 124I. The radiotracer was then tested for PET prediction of tumor responses to ICB therapy. Results: We identified galectin-1 (Gal-1), a member of the carbohydrate-binding lectin family, as a potential negative biomarker for ICB efficacy. We established that Gal-1 inhibition promotes a sensitive immune phenotype within the tumor microenvironment (TME) for ICB therapy. To assess the pre-ICB treatment status of the TME, a Gal-1-targeted PET radiotracer, 124I-αGal-1, was developed. PET imaging with 124I-αGal-1 showed the pretreatment immunosuppressive status of the TME before the initiation of therapy, thus enabling the prediction of ICB resistance in advance. Moreover, the use of hydrogel scaffolds loaded with a Gal-1 inhibitor, thiodigalactoside, demonstrated that a single dose of thiodigalactoside-hydrogel significantly potentiated ICB and adoptive cell transfer immunotherapies by remodeling the immunosuppressive TME. Conclusion: Our study underscores the potential of Gal-1-targeted PET imaging as a valuable strategy for early-stage monitoring of tumor responses to ICB therapy. Additionally, Gal-1 inhibition effectively counteracts the immunosuppressive TME, resulting in enhanced immunotherapy efficacy.

Structural insights into the ubiquitylation strategy of the oligomeric CRL2FEM1B E3 ubiquitin ligase.

Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been reported to be crucial for the regulation of their activities. However, the structural basis for its regulation and mechanism of its oligomerization are not fully known. Here, we present cryo-EM structures of oligomeric CRL2FEM1B in its unneddylated state, neddylated state in complex with BEX2 as well as neddylated state in complex with FNIP1/FLCN. These structures reveal that asymmetric dimerization of N8-CRL2FEM1B is critical for the ubiquitylation of BEX2 while FNIP1/FLCN is ubiquitylated by monomeric CRL2FEM1B. Our data present an example of the asymmetric homo-dimerization of CRL. Taken together, this study sheds light on the ubiquitylation strategy of oligomeric CRL2FEM1B according to substrates with different scales.

High-Sensitivity Optical Sensors Empowered by Quasi-Bound States in the Continuum in a Hybrid Metal-Dielectric Metasurface.

Enhancing light-matter interaction is a key requisite in the realm of optical sensors. Bound states in the continuum (BICs), possessing high quality factors (Q factors), have shown great advantages in sensing applications. Recent theories elucidate the ability of BICs with hybrid metal-dielectric architectures to achieve high Q factors and high sensitivities. However, the experimental validation of the sensing performance in such hybrid systems remains equivocal. In this study, we propose two symmetry-protected quasi-BIC modes in a metal-dielectric metasurface. Our results demonstrate that, under the normal incidence of light, the quasi-BIC mode dominated by dielectric can achieve a high Q factor of 412 and a sensing performance with a high bulk sensitivity of 492.7 nm/RIU (refractive index unit) and a figure of merit (FOM) of 266.3 RIU-1, while the quasi-BIC mode dominated by metal exhibits a stronger surface affinity in the biotin-streptavidin bioassay. These findings offer a promising approach for implementing metasurface-based sensors, representing a paradigm for high-sensitivity biosensing platforms.

CircPTEN-MT from PTEN regulates mitochondrial energy metabolism.

Phosphatase and tensin homolog (PTEN) is a multifunctional gene involved in a variety of physiological and pathological processes. Circular RNAs (circRNAs) are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins. However, PTEN-related circRNAs are largely unknown. Here, we report that circPTEN- mitochondria (MT) (hsa_circ_0002934) is a circular RNA encoded by exons 3, 4, and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism. CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), which regulates posttranscriptional gene expression in mitochondria. Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator (SRA) stem-loop interacting RNA binding protein (SLIRP) and inhibits the polyadenylation of mitochondrial mRNA, which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production. Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism. This study expands our understanding of the role of PTEN, which produces both linear and circular RNAs with different and independent functions.

Improved photosynthetic performance under unilateral weak light conditions in a wide-narrow-row intercropping system is associated with altered sugar transport.

Intercropping improves resource utilization. Under wide-narrow-row maize (Zea mays) intercropping, maize plants are subjected to weak unilateral illumination and exhibit high photosynthetic performance. However, the mechanism regulating photosynthesis under unilateral weak light remains unknown. We investigated the relationship between photosynthesis and sugar metabolism in maize under unilateral weak light. Our results showed that the net photosynthetic rate (Pn) of unshaded leaves increased as the level of shade on the other side increased. On the contrary, the concentration of sucrose and starch and the number of starch granules in the unshaded leaves decreased with increased shading due to the transfer of abundant C into the grains. However, sink loss with ear removal reduced the Pn of unshaded leaves. Intense unilateral shade (40% to 20% normal light), but not mild unilateral shade (60% normal light), reduced grain yield (37.6% to 54.4%, respectively). We further found that in unshaded leaves, Agpsl, Bmy, and Mexl-like expression significantly influenced sucrose and starch metabolism, while Sweet13a and Sut1 expression was crucial for sugar export. In shaded leaves, expression of Sps1, Agpsl, and Sweet13c was crucial for sugar metabolism and export. This study confirmed that unshaded leaves transported photosynthates to the ear, leading to a decrease in sugar concentration. The improvement of photosynthetic performance was associated with altered sugar transport. We propose a narrow-row spacing of 40 cm, which provides appropriate unilateral shade and limits yield reduction.

Identification of Seizure Onset Zone from Intracranial EEG Using Source Selection-Based Domain Adaptation.

For focal epilepsy patients, correctly identifying the seizure onset zone (SOZ) is essential for surgical treatment. In automated realistic SOZ identification, it is necessary to identify the SOZ of an unknown patient using another patient's electroencephalogram (EEG). However, in such cases, the influence of individual differences in EEG becomes a bottleneck. In this paper, we propose the method with domain adaptation and source patient selection to address the issue of individual differences in EEG and improve performance. The proposed method was evaluated on intracranial EEG data from 11 patients with epilepsy caused by focal cortical dysplasia. The results showed that the proposed method significantly improved SOZ identification performance compared to existing methods without domain adaptation and source patient selection. In addition, it was suggested that data from residual-seizure patients may have adversely affected estimation performance. Visualization of the prediction on MRI images showed that the proposed method might detect SOZs missed by epileptologists.

Antagonistic effects of N-acetylcysteine on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast cells.

Lead (Pb) is a heavy metal that can have harmful effects on the environment, which has severe cytotoxicity in many animal tissues. N-acetylcysteine (NAC) has antioxidant activity, reducing lead-induced oxidative stress and apoptosis, but its role in chicken cells is unknown. The current study explored the antagonistic effect of NAC on lead-induced apoptosis and oxidative stress in chicken embryo fibroblast (CEF). In this study, CEF was used as a model to measure the cytotoxic effects of lead nitrate at different concentrations, demonstrating a dose-dependent effect on CEF activity. Employing inverted microscopy, the investigation of morphological alterations in CEF cells was conducted. Fluorescence staining methodology enabled the assessment of reactive oxygen species (ROS) levels within CEF cells. Moreover, an enzyme-linked immunosorbent assay was utilized to detect the presence of oxidative damage indicators encompassing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) activity, malondialdehyde (MDA) content, and total antioxidant capacity (T-AOC) within CEF cells. Furthermore, the determination of the apoptosis rate of CEF cells was accomplished through the utilization of the Hoechst 33258 staining method in combination with the Annexin V-FITC dual staining method. By using RT-qPCR for detection, lead treatment increased expression of pro-apoptotic genes, caspase-3, and caspase-9, and reduced expression of anti-apoptotic genes, Bcl-2, and BI-1. Reduced antioxidant capacity was shown by increased ROS and MDA levels in CEF cells after lead treatment. The results showed that NAC inhibited the expression of caspase-3 and caspase-9 in lead-treated CEF cells, while NAC had a certain inhibitory effect on the relative expression of Bcl-2 and BI-1 mRNA in lead-induced CEF cells. NAC significantly reduced lead-induced oxidative damage and apoptosis. Overall, our results demonstrate a novel protective effect of NAC against lead-induced injury in chicken cells, providing a theoretical basis for future investigations of drugs that are effective in preventing lead poisoning in animals.

LORF9 of Marek's disease virus is involved in the early cytolytic replication of B lymphocytes and can act as a target for gene deletion vaccine development.

IMPORTANCE: Marek's disease virus (MDV) is a highly infectious and oncogenic virus that can induce severe T cell lymphomas in chickens. MDV encodes more than 100 genes, most of which have unknown functions. This work indicated that the LORF9 gene is necessary for MDV early cytolytic replication in B lymphocytes. In addition, we have found that the LORF9 deletion mutant has a comparative immunological protective effect with CVI988/Rispens vaccine strain against very virulent MDV challenge. This is a significant discovery that LORF9 can be exploited as a possible target for the development of an MDV gene deletion vaccine.

PTIR1 acts as an isoform of DDX58 and promotes tumor immune resistance through activation of UCHL5.

Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.

Critical role of VHL/BICD2/STAT1 axis in crystal-associated kidney disease.

Nephrolithiasis is highly prevalent and associated with the increased risk of kidney cancer. The tumor suppressor von Hippel-Lindau (VHL) is critical for renal cancer development, however, its role in kidney stone disease has not been fully elucidated until now. Here we reported VHL expression was upregulated in renal epithelial cells upon exposure to crystal. Utilizing Vhl+/mu mouse model, depletion of VHL exacerbated kidney inflammatory injury during nephrolithiasis. Conversely, overexpression of VHL limited crystal-induced lipid peroxidation and ferroptosis in a BICD2-depdendent manner. Mechanistically, VHL interacted with the cargo adaptor BICD2 and promoted itsd K48-linked poly-ubiquitination, consequently resulting in the proteasomal degradation of BICD2. Through promoting STAT1 nuclear translocation, BICD2 facilitated IFNγ signaling transduction and enhanced IFNγ-mediated suppression of cystine/glutamate antiporter system Xc-, eventually increasing cell sensitivity to ferroptosis. Moreover, we found that the BRAF inhibitor impaired the association of VHL with BICD2 through triggering BICD2 phosphorylation, ultimately causing severe ferroptosis and nephrotoxicity. Collectively, our results uncover the important role of VHL/BICD2/STAT1 axis in crystal kidney injury and provide a potential therapeutic target for treatment and prevention of renal inflammation and drug-induced nephrotoxicity.